Method for preparing 6-substituted penicillins by replacement of oxygen containing groups

ABSTRACT

Disclosed is a method for replacing 6-lower alkanoyloxy and 6aroyloxy groups from penicillins with other lower alkanoyloxy, lower alkoxy, aryloxy, amino, lower alkyl amino and azido moieties.

United States Patent [191 Dolfini et al.

[451 Feb. 25, 1975 METHOD FOR PREPARING 6-SUBSTITUTED PENICILLINS BYREPLACEMENT OF OXYGEN CONTAINING GROUPS [22] Filed: Dec. 6, 1972 [21]Appl. No.: 312,470

[52] US. Cl. 260/239.1, 424/271 [51] Int. Cl C07d 99/16 [58] Field ofSearch 260/243 C, 239.1

[56] References Cited UNITED STATES PATENTS 3,733,320 5/1973 Pines et al260/243 C Primary Examiner-Nicholas S. Rizzo Attorney, Agent, orFirm-Lawrence S. Levinson; Merle J. Smith; Stephen B. Davis [57]ABSTRACT Disclosed is a method for replacing 6-lower alkanoyloxy and6-aroyloxy groups from penicillins with other lower alkanoyloxy, loweralkoxy, aryloxy, amino, lower alkyl amino and azido moieties.

4 Claims, No Drawings 1 METHOD FOR PREPARING asunsrrrurgy P EN I OILLINSBY REPLACEMENT OF OXYGEN CONTAINING GROUPS Penicillins are ofconsiderable interest to the pharmaceutical industry. Presentlycompounds of this type are being employed as potent antimicrobials. Asin the case of the cephalosporins and tetracyclines, researchers are nowtrying to improve on the activity of these antibiotics by modifying thenaturally occurring penicillins. Unfortunately, most antibiotics arequite complex and therefore simple reactions cannot be utilized tointroduce the desired modifications. Usually considerable effort must beextended to devise a method for modifying such complex entities. Hereinis described such a procedure which gives rise to useful antibacterialpenicillins.

This invention relates to a method for the conversion of penicillins ofthe formula:

into compounds of the formula:

S 3 R :t:cn

/ N co R wherein R, is acylamino, a Schiff base such as benzalimino, ora substituted Schiff base; R is lower alkanoyloxy or aroyloxy orsubstituted aroyloxy; R is hydrogen, or a cation such as Na Li Ca K*,

such as t-butyl, trichloroethyl, trimethylsilyl or pmethoxybenzyl; and Ris lower alkoxy, other lower alkanoyloxy, aryloxy, azido, amino, monoanddilower alkyl amino by the use (Sf certain mercury,

silver, and thallium salts and an appropriate source of R,, such as alower alkylalcoholfa phenol or its salt, lower alkanoic acid or saltthereof, amines, lower alkyl amines, di-lower alkyl amines or metalazides.

Acyl is defined in this invention as:

R -d (c11 phenoxy, and phenylthio may be one or more of the following,lower alkyl, lower alkoxy, halo. nitro, amino and trifluoromethyl and nis either 0 or an integer from 1 to 4.

R CO wherein R is hydrogen, amino, phenyl, substituted phenyl, loweralkoxy, thienyl, substituted thienyl, phenoxy, lower alkylthio,substituted phenoxy, ,B-lower alkenyl, B-lower alkylthio lower alkenyl,B-lower alkoxy lower alkenyl and B-lower alkenyloxy lower alkyl, whereinthe substituents on the thienyl, phenyl and phenoxy may be one or moreof the following: lower alkyl, lower alkoxy, halo, nitro, amino andtrifluoromethyl.

Lower alkyl is defined as a branched or straight chain having from oneto six carbon atoms. This definition also applies to terms incorporatinglower alkyl with other groups, such as aryl lower alkyl which isintended to mean an aryl group linked to an alkyl group having one tosix carbon atoms.

Aryl is defined as phenyl and aand B-naphthyl.

Substituted as in substituted Schiff base, substituted aryl orsubstituted benzalimino is intended to mean unless specifically definedotherwise as monoor disubstituted wherein said substituents may be loweralkyl, lower alkoxy, nitro, chloro, fluoro or trifluoromethyl.

Numerous modifications of the naturally occurring penicillins havealready been made in an effort to en-,

hance antimicrobial activity with a certain degree of success beingachieved. One of the positions ofthe penicillin nucleus which a numberof researchers have focused upon as a place for introducing newgroupings is the 6-position. Since substituents on the 6a-position tendto demonstrate higher degrees of antimicrobial activity than6/3-substituents, attempts to devise new syntheses for introducingsubstituents into this position are generally directed to theintroduction of 6asubstituents.

This invention teaches how one may convert the readily prepared6-acyloxy derivatives to compounds wherein the 6-acyloxy group isreplaced by lower alkoxy, aryloxy, other lower alkanoyloxy, azido, aminoand lower alkylamino groups.

The above described starting materials of the structure R CH R II:CH A N2 3 wherein R through R are as previously defined are converted into thecompounds of this invention having the formula:

(ic form) and the anions are preferably one ofthe following: loweralkoxy, loweralkanoyloxy, cyano, nitrate, fluoro, bromo, sulphate andchloro.

For R to be lower alkoxy, the reagent may be the corresponding loweralkanol. In turn, lower alkanoyloxy is introduced by utilizing thecorresponding lower alkanoic acid or a heavy metal salt thereof,(mercury, silver, etc.); aryloxy is introduced by utilizing a phenol orsalt thereof, azido is introduced by the use of an azide salt, such aspotassium or sodium azide in the presence of catalyst, and amino isintroduced by the use of an excess of amine in the presence of catalyst.

The reactions of this invention are preferably conducted in inertsolvents, such as dimethoxyethane, dioxane, dimethylformamide, andtetramethylurea at temperatures from about 10 to about 1 10C, preferablyfrom about to about 70C. However, where a lower alkoxy group is beingintroduced, the corresponding alcohol may be employed as the reactionsolvent. The replacement reactions of this invention take place at arelatively rapid rate so that the reaction time required is usually fromabout a few minutes to several hours at ambient temperature.

While this reaction is of a general nature, the preferred compounds tobe prepared by the process of this invention are those of the formula:

4 T3 R1 (S CH3 0 N CO R 6a-alkanoy1oxyor 6q aryloxy-6-benzaliminopenicil;

lanic acid or. its ester, one obtains almost ems ively 6aR-substitution, whereas if a 6a-alkanoyloxyor 611- aryloxy-6-acylaminopenicillanic acid compound is employed, the'relative amounts of isomersobtained are determined by the nature of the solvent or catalyst used.

This invention is intended to encompass the preparation of both 60: and6B isomers, in addition to those which may also be encountered at othersites in the compounds of this invention.

The penicillins which may be prepared by this invention are usefulagainst gram-positive bacteria, such as Staphylococcus aureus andStreptococcus pyogenes, and especially against gram-negative bacteriasuch as Escherichia coli and Proteus vulgaris.

EXAMPLES EXAMPLE 1 a-Methylthio-6-benzaliminopenicillanic Acidp-Methoxybenzyl Ester Method A. To a stirred solution of 6-benzaliminopenicillanic acid p-methoxybenzyl ester (1.04 g, 2.43 mmol)in 'dimethoxyethane (150 ml) at 10 is added potassium t-butoxide (272mg, 2.43 mmol). The orange solution is stirred for two minutes,

and methyl methanethiolsulfonate (306 mg, 2.43 mmol) is added. Aftrstirring for 1 hour at l0, the mixture is poured into pH 6.6 buffer (300ml) and extracted with ethyl acetate. Evaporation of the dried (MgSO)extract gives 1.10 g of XVII yield) as a yellow oil. The oil has: ir(CHCl 1765 (,B-lactam C=O), 1740 (ester C=O) and 1610cm (C=N); pmr DCC118.67 (3H,s,CH 8.57 (3H,s,-CH 7.83 (3H,s,'SCH 6.37 (3H,s,--OCH 5.57(lH,s,C-3), 4.93 (2H,s,-OCH 4.43 (lH,s,C-S), 2.93 (9H,m,aromatic), and1.33 (lH,s,CH=N) mass spec trum molecular ion at m/e 470, base peak atm/e 12].

Method B. Methylsulfenyl Chloride Procedure The procedure in part A isfollowed using 2.43 mmol By following the procedure in Example 1, butsubstituting 6-benzaliminopenicillanic acid methyl ester for the Schiffbase substrate, the desired product is obtained.

EXAMPLE 3 6a-Phenylthio-6-(p-nitrobenzalimino)penicillanic Acidp-Methoxybenzyl Ester By following the procedure in Example 1, method B,but substituting 6(p-nitrobenzalimino)penicillanic acid p-methoxybenzylester for the Schiff base substrate and phenylsulfenyl chloride formethylsulfenyl chloride, the desired product is obtained.

EXAMPLE 4 6a-Ethylthio-6-( p-methoxybenzalimino)penicillanic Acidp-Methoxybenzyl Ester By following the procedure in Example 1, method B,but substituting 6-(p-methoxybenzalimino)penicillanic acidp-methoxybenzyl ester for the Schiff base substrate and ethylsulfenylchloride for methylsulfenyl chloride, the desired product is obtained.

EXAMPLE 5 6a-Methylthio-6-phenoxyacetamidopenicillanic Acidp-Methoxybenzyl Ester To a solution of the methylthio Schiff base ofExample l (104 mg, 2.45 mmol) in 4 ml of dimethoxyethane is addedphenoxyacetyl chloride (33.5 ml, 2.45 mmol), followed by water (4 ml,2.45 mmol). The mixture is stirred for 40 minutes at room temperatureand poured into water. Extraction with ethyl acetate gives a yellow oil(61 mg) that is purified by tlc on Quantum PQlF silica gel in thesystem, hexane-ethyl acetate (4:1 to give 32 mg (25% yield) of thedesired product as a colorless oil with: ir (CHCl 1780 (B-lactam C=O),1745 (ester C=O), and 1692 (amide C=O) pmr (DCCl 18.67 (3H,s,CH 8.53(3H,s,Cl-l 7.73 (3l-l,s,--SCH 6.20 (3H,s,OCH 5.63 (lH,s,C-3), 5.50(2H,'s,Cl-l C=O), 4.90 (2H,s,OCl-1 4.45 (lH,s,C-S), 3.00(9l-l,s,aromatic), and 1.93 (lH,m,Nll).

The desired amide is also prepared in 20% yield by treating themethylthio Schiff base of Example 1 with equivalent amounts ofp-toluenesulfonic acid monohydrate, triethylamine, and phenoxyacetylchloride in EtOAc.

EXAMPLE 6 6a-Methylthio-6-phenylacetamidopenicillanic Acidp-Methoxybenzyl Ester The 6a-methylthio amide is obtained in 14% yieldby the procedure described for the preparation of methylthio amide inExample 5, but substituting phenylacetylchloride for phenoxyacetylchloride. The desired product has: ir (CHCl 1775 (,B-lactam C=O) 1740esETt fiT an rssomz'ifirm oiifir (DCCI 18.70 (3H,s,-CH 7.83 (3H,s,SCH

(2H,.s,CH

6.18 (3H,s,OCH 5.63 (1H,s,C-2), 4.88 (2H,s,OCH 4.45 (1H,s,C-5), and3.30-2.57 (H,m,N-H and aromatics).

EXAMPLE? 6oz-Methylthio-6-(2-thienyl)acetamidopenicillanic AcidTrichloroethyl Ester By following the procedure in Example 5 butsubstituting 6a-methylthio-6-benzaliminopenicillanic acid trichloroethylester for the Schiff base and (2- thienyl)acetyl chloride forphenoxyacetyl chloride, the desired product is obtained as an amorphousresidue.

EXAMPLE 8 6a-Acetoxy 6-phenylacetamidopenicillanic Acid p-MethoxybenzylEster a. To a suspension of the 6a'-methylthio ester (Example 6) (1.5mmol) in 5 ml of dimethoxyethane is added mercuric acetate (1.5 mmol).The mixture is stirred under nitrogen for 20 minutes at roomtemperature. The precipitate is filtered and washed with dimethoxyethaneyielding a pale yellow powder. The filtrate is evaporated to a residuethat is taken up in benzenewater. The benzene layer is washed withwater, dried (Na SO and evaporated to give the above named ester.

b. To 109 mg (0.25 mmole) ofmethylthio amide (Example 6) in 2 ml ofacetic acid is added 164 mg (2 mmolcs) of sodium acetate, followed by 80mg (0.25 mmole) of mercuric acetate. The mixture is stirred for minutesat room temperature, and the acetic acid is removed in vacuo. Theresidue is taken up in benzene and water. The benzene layer is washedwith aqueous sodium chloride solution, dried (Na SO and evaporated togive the ester as a residue.

EXAMPLE 9 6a-Methylthio-6-benzaliminopenicillanic Acid and6a-Methylthio-6-aminopenicillanic Acid To a slurry of6-benzaliminopenicillanic acid (5.1 l g, 16.9 mmol) in drydimethoxyethane (200 ml) at room temperature is added potassiumt-butoxide (1 89 g, 16.9 mmol). The mixture turned orange, and completesolution occurred after 3 minutes. Trimethylsilyl chloride (1.83 g, 16.9mmol) is added, and the mixture is stirred for 12 minutes as it cools to-l0. Potassium tbutoxide (1.89 g, 16.9 mmol) is added, and the solutionturns red. After 15 minutes, methyl methanethiosulfonate (2.12 g. 16.9mmol) is added, and stirring is continued for 30 minutes at 10. Thedimethoxyethane is removed in vacuo, and the residue is taken up in pH7.8 phosphate buffer and EtOAc. The EtOAc layer is discarded, and theaqueous layer is washed repeatedly with EtOAc. The EtOAc washings arediscarded, and the aqueous part is layered with EtOAc and adjusted to pH4.0 with dilute HCl. Extraction with CHCl and EtOAc gives a residue,after drying (MgSO and concentration. Trituration of the residue withCHCl gives 240 mg of 6-a-methylthio-6-aminopenicillanic acid as a solidand a supernate. Evaporation of the supcrnute gives 650 mg of6-a-methylthio-6-benzylimino penicillanic acid (19% yield) as an oil.

Adjustment of the pH 4 aqueous solution to pH 1.9 and extraction withEtOAc gives a further quantity of the amino acid (800 mg), for a totalyield of 23%.

The amorphous amino acid has: ir (Nujol) 1755 (,B-lactam C=O), and1715cm' (acid C=O); mp 172-176 (dec); pmr (DMSO-d r860 (3H,s,CH 8.53(3H,s,Cl-l 7.85 (3H,s,SCH 5.82 (1H,s,C- 5), and 3.90 (3H,broad,NH massspectrum, molecular ion m/e 262, base peak m/e 160. Anal. Calcd. for C HN O S C,41.22; H,5.38; N,l0.68. Found: C,4l.88; H,5.78; N,10.00.

The Schiff base has: it (CHCl 1760 (B-lactam C=O), 1720 (COOH), and 1622cm (C=N); pmr (DCCl 78.43 (6H,s,2-CH 7.73 (3H,s,SCH 5.60 (1H,s,C-3),4.45 (1H,s,C-5), 4.60 (5H,m,aromatics), 1.57 (1H,broad,COOH); massspectrum of trimethylsilyl ester, molecular ion at m/e 422.

EXAMPLE 10 6a-Methylthio-6-phenoxyacetamidopenicillanic Acid To astirred suspension of the methylthio amino acid from Example 9 (127 mg,0.485 mmol) in dimethoxyethane (12 ml) is addedN,O-bistrimethylsilylacetamide ml, 0.485 mmol). Solution occurs after 15minutes of stirring. Triethylamine (68 ml, 0.485 mmol) and phenoxyacetylchloride (67 ml, 0.485 mmol) are added sequentially, and the mixture isstirred for 1.5 hour at room temperature and concentrated under vacuumto a residue. The residue is taken up in EtOAc-H O, and the water layeris discarded. Water is added to the EtOAc layer, and the pH is adjustedto 7.5. The EtOAc layer is discarded, and the aqueous solution iscovered with EtOAc and adjusted to pH 3.2 with dilute HCl. The resultingEtOAc extract is dried (Na SO,) and evaporated to a residue. Triturationwith hexanebenzene gives 72 mg of amorphous product (38% yield); ir(CHCl 1780 (B-lactam C=O), 1730 (COOH), and 1690cm (amide C=O), pmr(DCCl)1-8.47 6H,s,2CH 7.70 (3H,s,-SCH 5.50 (1H,s,C-3), 5.33 (2H,s,O-CH 4.35(1H,s,C- 5), 2.83 (5H,m,aromatics), and 2.30 (1H,s,N-ll); mass spectrumof trimethylsilyl ester, molecular ion at m/e 468.

EXAMPLE 1 l 6-Methylthio-6-phenylacetamidopenicillanic Acid This acid isobtained in 78% yield by the method described for the preparation of theacid of the previous example, but by substituting phenylacetyl chloridein place of phenoxyacetyl chloride. The amorphous acid 7 has: ir (CHCl1777 (,B-lactam C=O), 1725 (COOH),

and 1680cm (amide C=O); pmr (DCCl r8.57 (6H,m,2CHa), 7.83 (3H,s,SCH3),6.38

(2H,s,-CH 5.67 (lH,s,C-3), 4.48 (lH,s,C-5), 2.67 (5H,m,aromatics), 2.17(lH,m,N-H); mass spectrum of trimethylsilyl ester, molecular ion at m/e452.

EXAMPLE l2 A mixture of 0.14 mmole of 6a-acetoxy compound (Example 8)and 0.14 mmole of mercuric acetate in 0.5 ml of dirnethylformamide isstirred under nitrogen at room temperature for 25 minutes. The mixtureis taken up in water and benzene, and the benzene layer mately 50:50mixture of 6d-acetoxy and ofl-acetoxy epimers (Example 12) in 3 ml ofmethanol is added 332 mg (1.04 mmole) mercuric acetate. The mixture isstirred under nitrogen at room temperature for40 minutes. The methanolis removed under reduced pressure, and the residue is taken up inbenzene and water. The benzene layer is washed with water, dried (Nu SOand evaporated to give a residue consisting of 6amethoxyand6B-mcthoxy-6- phenylacetamidopenicillanic acid esters.

EXAMPLE l6 6-Benzalimino-6a-methoxypenicillanic Acid is washed twicewith water, dried (Na- 50 and evapo- 15 M h b l E rated in vacuo to givea residue consisting of approxiet oxy enzy Ster mately equal quantitiesof the 6-oz and 6-B acetoxy epi- A mixture of mercuric acetate (1 mmol)and the 6- mers. acetoxy Schiff base (1 mmol) from Example 13 inmethanol is stirred for 30 minutes at room tempera- EXAMPLE 13 ture. Themixture is evaporated to a residue which is6-Benzalimino-6a-acetoxypenicillanic A id taken up in benzene and water.The benzene layer is -M h b l E t washed with water, dried (Na SO andevaporated to A mixture ofmercuric acetate g 0 135 mmol) a residue.Crystallization of the residue from methanol t d and the methylthioSchiff base from Example 1 (0.124 gwes he eslred product mmol) indimethoxyethane (20 ml) is stirred at room EXAMPLE l7 temperature forminutes. Dilution with anhydrous 6 BenZa1imino 6a ethoxypenicinanic Acidether (100 ml) and filtration through Cel1te removes p MethoxybenzylEster insoluble material. After stripping solvent under re- Th d d d E I16 d duced pressure, the residue is taken up in ether and 30 re 2 ai g mxampde to washed with water. The organic layer is treated with g g a i 9f ace Norite and the volume of solvent is reduced yielding c l ase mmXamp e ls Y yzed p ute d d ethanol and catalyzed by the addition of 1equivalent the above name pro of mercuric acetate. After the workup, the6a-ethoxy E E 14 Schiff base is obtained. 6a-Azido and6B-azido-6-phenylacetamidopenicillanic EXAMPLE l8 Acld p'MethoxybenzylEsters General Procedure for the metal catalyzed solvolysis To 63 mg(0.14 mmole) of a-acetoxy compound of the 6-alkanoyloxyor6-aroyloxy-penams (I) shown (Example 8) in 0.4 ml of dimethylformamideis added 40 m abl I- 92 mg (1,4 l f di id f ll d b mg To a solution orsuspenston of the 6-alkanoyloxyor (0.14 mmole) of mercuric acetate. Themixture is y y-pe In the lfldlcated anhydrous stirred under nitrogen for30 minutes at room tempera- Vent System, added equlvfllem e l ye ture.The solvent is removed under reduced pressure, and equivalents ofOrganic e 1f lndlcated and the residue is taken up in benzene and waterThe 45 Table l. The heterogenous mixture is stirred, preferably benzenelayer is washed three times with water, dried finder e e at thetemperature e (Na s04) and evaporated yielding 60 mg of residue in TableI. The reaction is best followed to completion Consisting of and bymonitoring the mixture by thin layerchromatographenylacetamidopenicillanic acid p-methoxybenzyl esphy Smcereacnon found to ters 5O moval of the solvent system in vacuo, theresidue 18 diluted with an organic solvent, which is immiscible withEXAMPLE {5 water, and filtered to remove insoluble materials. The

. solution is washed with dilute aqueous sodium bicar- B p lzigi g z sijigi igg gfizfifg figi bonate solution and water, the organic layer isdried, 8 b and solvent lS removed under reduced pressure. An

et oxy enzy Sters amorphous residue is obtained containing the appropri-To a solution of 465 mg (1.04 mmole) of an approxiate pcnam derivativeindicated in Table l.

ELIE-ELM R R I 13 Catalyst solvent Temp.

-cn -conu -OAc(G) t-btityl OAc(CH-B) Hg 0A DMF 25 TABLE I (continued) RR R 1]; 7 Catalyst Solvent Temp.

@cn-couamm t-but yl -n a+a) Hg(OAc) NaN 25 DMF OAc (a) CH30@-CH2 -N3(0+5) Hg (OAc) 2 NaN 25 a E S j-CH -CONH DMF li -cu CONH oAc (a) t-butyl(CH3 2N- Hg (cm) 2 (c14 ZNH, 2,

DMF

com: 0mm) t-butyl -N +5) Hg(0CH NaN DMF O2N-CH=N OAc (a) t-butyl 0on H9M) 2 CHH 2 5 J I o @CPFN 0A: CH O-O-CH oca (a) Hg (0on 2 CH3OH 25 NC=NOAc(C!) t-butyl oca ca (a) Hg(OAc) on CH on 25--- g 2 3 2 3 2 800 p i vNaN O2N--CH=N OAc (a) t-butyl m Ia Hg(OAc) DMF 25 \CH=N- 0Ac( 1) t-butyl(CH N- Hg(0Ac) (ca J, NH, 25 3 2 2 I 3 2 (MB) DMF What is claimed is: RS CH 1. A process for the preparation of compounds of the 1 3 formula:CH

4 S CH and azido; and R is selected from the group consisting.

of hydrogen, methyl, t-butyl, trichloroethyl, trimethylsilyl,p-methoxybenzyl, and a cation; which comprises reacting a compound offormula:

wherein R and R are as defined above and R is lower alkanoyloxy; with acompound selected from the group consisting of lower alkyl alcohols,phenol, lower alkanoic acid or its heavy metal salt, sodium azide andpotassium azide at a temperature of from about l0 to about 1 10C in thepresence ofa catalyst selected from the group consisting of mercuricacetate, mercuric chloride, silver acetate, silver tetrafluorborate,thallium acetate, and dimethoxy mercury.

2. The process of claim 1 wherein R is acetoxy.

3. The process ofclaim 2 wherein R is selected from the group consistingof methoxy, ethoxy, propionyloxy, phenoxy and azido.

4. The process of claim 2 wherein said catalyst is selected from thegroup'consisting of mercuric acetate,

dimethoxy mercury and silver tetrafluoroborate.

UNITED STATES PATENT OFFICE CETEHGATE CORECTION PATENT NO. 1 3 65 DATEDFeb. 25, 1975 INVENTOR(S) Joseph Edward Dolfini et al.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Columns 9 and 10, Table I, first line under the heading "R 'cr1 -com1"should be deleted and -UCH2CONH- should be inserted in its place; firstline under the heading "R "t-butyl" should be deleted and CH O--CHshould be inserted in its place; first line under the heading "Solvent",

"CH OH" should be deleted and --AcOH-- should be inserted in its place.

Signed and sealed this 15th day of July 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C, MASON Commissioner of Patents Attesting OfficerI and Trademarks

1. A PROCESS FOR THE PREPARATION OF COMPOUNDS OF THE FORMULA:
 2. Theprocess of claim 1 wherein R2 is acetoxy.
 3. The process of claim 2wherein R4 is selected from the group consisting of methoxy, ethoxy,propionyloxy, phenoxy and azido.
 4. The process of claim 2 wherein saidcatalyst is selected from the group consisting of mercuric acetate,dimethoxy mercury and silver tetrafluoroborate.